A Single-Cell Atlas of Uterine Carcinosarcoma from Diverse Ancestries

Subhash, Santhilal, Bammert, Marie-Thérèse, Yueh, Brian, Chu, Timothy, Barbi, Mali, Alici, Aybuke, Eskiocak, Onur, Ozler, Kadir A, Nizam, Aaron, Katcher, Arielle, Chung, Charlie, Shah, Vyom, Ozcelik, Elif, Robine, Nicolas, Frimer, Marina, Goldberg, Gary L, Beyaz, Semir (April 2026) A Single-Cell Atlas of Uterine Carcinosarcoma from Diverse Ancestries. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Uterine carcinosarcoma (UCS) is an aggressive endometrial malignancy characterized by epithelial-mesenchymal plasticity, early metastasis, and poor therapeutic response. However, its single-cell organization and microenvironmental interactions remain incompletely defined, particularly in patients of African ancestry who are underrepresented in genomic datasets despite a disproportionate disease burden. Here, we generate a single-cell transcriptomic atlas of UCS from a diverse cohort enriched for patients of African ancestry, integrated with whole-genome sequencing. We identify pronounced inter-patient heterogeneity and resolve epithelial-like, mesenchymal-like, transitional, and stem-like malignant states. Copy-number and trajectory analyses reveal multiple subclones linked along epithelial, progenitor-like, and mesenchymal programs, consistent with metaplastic transitions. Compared to normal endometrium, primary tumors exhibit epithelial-mesenchymal-transition (EMT), mTORC1, and glycolytic programs, whereas metastases show enhanced TNFα-NFκB signaling linked to invasion. The tumor microenvironment comprises diverse immunosuppressive myeloid states and heterogeneous cancer-associated fibroblast populations, including pericyte-like and matrix-remodeling subsets that act as communication hubs via chemokine and immune-checkpoint signaling. These data define the UCS cellular ecosystem in which malignant plasticity is coupled to stromal-immune cell remodeling in a patient cohort of diverse ancestries.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
CSHL Authors:
Communities: CSHL labs > Beyaz lab
CSHL labs > Meyer Lab
CSHL Post Doctoral Fellows
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 24 April 2026
Date Deposited: 11 May 2026 12:47
Last Modified: 11 May 2026 12:47
PMCID: PMC13131811
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42193

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